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Date of Award

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RU Laboratory

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Abstract

Stressful life events have been implicated clinically in the pathogenesis of major depression, but the neural substrates that may account for this observation remain poorly understood. Attentional impairments symptomatic of depression are associated with structural and functional abnormalities in the prefrontal cortex. In three parallel rodent and human neuroimaging studies, this project assessed the effects of chronic stress on prefrontal cortical structure and function and the behavioral correlates of these changes. The first study used fMRI to elucidate the precise computational contributions of frontoparietal circuitry to attentional control in human subjects, using a task that could be adapted for rats. The results confirmed that the contributions of dorsolateral frontoparietal areas to visual attentional shifts could be dissociated from the regulatory influences of more ventrolateral areas on stimulus/response mappings, in a manner consistent with studies in animal models. They also indicated that anterior cingulate and posterior parietal cortex may act in concert to detect dissociable forms of information processing conflicts and signal to dorsolateral prefrontal cortex the need for increased attentional control. Stress-induced alterations in these regions and in the connections between them may therefore contribute to attentional impairments. The second study tested this hypothesis in rats by examining whether chronic stress effects on medial prefrontal (mPFC) and orbitofrontal (OFC) dendritic morphology underlie impairments in the behaviors that they subserve. Chronic stress induced a selective impairment in attentional control and a corresponding retraction of apical dendritic arbors in mPFC. By contrast, stress did not adversely affect reversal learning or OFC dendritic arborization. These results suggest that prefrontal dendritic remodeling may underlie the attentional deficits that are symptomatic of stress-related mental illness. The third study was designed to extend these findings to human subjects, using the techniques developed in Study 1. Accordingly, chronic stress predicted selective attentional impairments and alterations in prefrontal functional coupling that were reversible after four weeks. Together, these studies outline in broad strokes a mechanistic model by which chronic stress may predispose susceptible persons to the attentional impairments that are characteristic of major depression. Future studies will assess the roles of serotonin and neurotrophins in mediating these changes.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.